The long term objective of this proposal is to characterize those cell surface components involved specifically in transplantation and the immune response, using immunochemical and biological analyses. To accomplish this goal, we plan to prepare xenoantibody directed against non-allogeneic determinants on fragments derived from soluble human histocompatibility antigen (HL-A), the latter isolated from th- plasma membranes of lymphocytes. Anomalies among alloantigenic activity, lymphocyte stimulation, and the cell-mediated response, suggest that these biological phenomena are functions of separate, but linked genes. Alloantibody is produced only to the serologically active allogeneic site, HL-A, and is not produced to the gene product(s) governing the mixed lymphocyte reactions (MLR). In contrast, xenoantibody, being of a broader specificity, should provide markers for portions of the HL-A-bearing molecule other than the alloantigenic site, as well as for separate molecules relating to diverse biological functions, such as mixed lymphocyte stimulation. Subcellular fractionation procedures, along with xeno- and alloantibody, will provide the means for determining the site of synthesis and possibly the sequence of assembly of various components of the molecule. Genetic linkage of Ir genes to chromosomal histocompatibility regions has suggested a role for the latter in the immune response. A functional linkage has also been suggested by the ability of anti-histocompatibility alloantibody to abrogate certain Ir functions. Well characterized xenoantibody may provide a means for defining and controlling different expressions of the immune response.